| dc.description.abstract | Prader-Willi syndrome (PWS) is characterised by
obesity, short stature, small hands and feet, neonatal
hypotonia with difficulty in feeding at birth,
hypogonadism and eye problems. At about two years of
age the feeding difficulties with poor suck are gradually
replaced by hyperphagia and obsession with food,
leading to the obesity. In addition to developmental
delay which is manifested by short stature, small hands
and feet, growth hormone deficiency and
hypogenitalism/hypogonadism, there are also
behavioural characteristics including learning
disabilities, temper tantrums, aggression, repetitive
speech, obsessive compulsive behaviour, sleep disorder
and skin picking (Cassidy and Driscoll, 2009). This
disparate collection of symptoms led Holm et al (1993)
to define the major and minor characteristics which
allowed a clinical diagnosis of this the most common
genetic form of obesity. Consensus diagnostic criteria
were defined and weighted scores in which the major
criteria were awarded one point and the minor criteria
half a point calculated. A score of 8 or more is clinically
diagnostic for PWS.
The majority of people with PWS have a paternally
derived deletion of approximately 5-7Mb in 15q11-q13,
others have maternal disomy of chromosome 15
(UPD15mat) and a minority have a defect of the
imprinting centre located in exon 1 of the SNRPN gene
which leads to a maternal imprint on the paternally
derived chromosome. Any of these abnormalities will
result in loss of the paternal contribution to the Prader-
Willi syndrome critical region (PWSCR), demonstrated
by loss of a paternally derived unmethylated band at the
imprinting centre and a lack of expression of the SNRPN
gene. Although these do not differentiate between the
different genetic types of PWS they are diagnostic for
the syndrome (Cassidy and Driscoll, 2009; Ramsden et
al, 2010; Zeschnigk et al, 1997).
Within 15q11-q13 the complex imprinted
SNURF/SNRPN gene hosts several untranslated snoRNA
genes located within intronic sequences. The finding of
a microdeletion involving SNORD116 in a boy with PWS
led to the identification of this snoRNA as the candidate
gene for the syndrome (Sahoo et al, 2008).
In the course of a large study of PWS in the UK
(Whittington et al, 2001; Soni et al, 2007) three people
were identified who fulfilled the criteria for a clinical
diagnosis of the syndrome but not the genetic
laboratory diagnostic criteria.
The Affymetrix Cytogenetics Whole-Genome 2.7M array
while providing high resolution whole genome coverage
reliably detects changes in copy number. Deletions
and/or duplications present in all three participants if
involved in annotated genes could potentially
contribute to the Prader-Willi-like phenotype.
Candidate genes can subsequently be evaluated to
estimate their transcription levels and compared with
those shown by people with PWS and with unaffected
individuals. | en |
